1. Field of the Invention
This invention relates to a method for enhancement of delivery of bupropion by administration via the nasal route, and methods of treatment comprising intranasally administering an effective amount of bupropion to prevent or treat withdrawal symptoms associated with smoking nicotine to a patient in need of such prevention or treatment and for the treatment of depression.
2. Description of the Related Art
Bupropion (1-[3-Chlorophenyl]-2-[(1,1-dimethylethyl)amino]-1-propanone) is a relatively dopamine-specific antidepressant of the aminoketone class (FIG. 1). It is chemically unrelated to the classical tricyclic antidepressants, but its therapeutic efficacy is comparable to the tricyclic antidepressant. In addition to its antidepressant properties, bupropion has been found to curb the craving and withdrawal symptoms tobacco smokers face when they quit (Ferry, L. H. et al. (1994) J. Addict. Dis. 13:249; Hurt, R. D. et al. (1997) N. Engl. J. Med. 337:1195). Bupropion was approved for use as an antidepressant by the Food and Drug Administration in 1989. It is currently marketed under the trade names Wellbutrin.RTM. (Burroughs Wellcome) and Zyban.RTM. (Glaxo-Wellcome).
Bupropion is well absorbed from the gastrointestinal tract after oral administration and is extensively metabolized in rat and man prior to excretion (9,10). Evidence suggests that bupropion has fewer autonomic and cardiovascular side effects than the tricyclic antidepressants (3-6). The three principal metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion appear to have slower clearance than bupropion, therefore they tend to accumulate to a greater extent than the parent drug during chronic bupropion therapy (10). It has been suggested that during chronic bupropion therapy, high hydroxybupropion concentrations may be associated with poorer clinical outcome (11,12). Furthermore, bupropion therapy is associated with seizures in approximately 0.4% of the patients treated with doses up to 450 mg/day. The incidence of seizures may exceed those of other antidepressants by up to fourfold, increasing to approximately tenfold at doses of 450-600 mg/day (7,8).
Combination therapy is often necessary in the treatment of mood disorders. Nevertheless, there are few data available regarding interactions between bupropion and other drugs. Clinical evidence suggests that the co-administration of fluoxetine (Prozac) and bupropion may yield delirium (13) and seizures (14) and that fluoxetine may increase hydroxybupropion and threohydrobupropion concentrations (15-18). Spontaneous postmarketing reports to the FDA are consistent with the possibility that fluoxetine inhibition of bupropion metabolism might yield seizures at lower bupropion dosages (19).
The absolute bioavailability of an oral dose in man has not been determined because an intravenous formulation for use in humans is not available. The absolute bioavailability of bupropion in animals is around 5% (20). Following oral administration of 200 mg of bupropion, 87% and 10% of the radioactive doses were excreted in the urine and feces, respectively, in man (21, 22). Plasma radioactivity concentration-time data obtained in the single-dose .sup.14 C metabolism study suggested that extensive presystemic elimination occurred in humans (21). Hence, the absolute bioavailability of an oral does of bupropion in man is expected to be low. Oral administration of bupropion is known to result in numerous dose-dependent adverse side effects, including seizure, headache/migraine, insomnia, dry mouth, dizziness, excessive sweating, anorexia, weight loss, constipation, sedation, tremor, and agitation (7). It is also reported that, due to its extensive first pass metabolism, high levels of bupropion metabolites may be associated with poor clinical outcome due to toxic effects involving dopaminergic systems (11).
Therefore, in view of the aforementioned deficiencies attendant with prior art methods of bupropion administration, it should be apparent that there still exists a need in the art for a safe and convenient method of administering bupropion to patients at safe and effective doses.